In human skin, epidermal melanocytes play a crucial role in photoprotection mainly due to their ability to synthesize melanin. Melanocytes have an extremely low proliferative capacity, thus their survival in the epidermis is crucial for cutaneous photoprotection. However, it is becoming clear that the risk for skin cancer is not simply determined by melanin content in the skin, but rather by the ability of the metanocyte to maintain genomic stability in the face of exposure to ultraviolet radiation, to prevent malignant transformation into melanoma. Endothelin-1 (ET-1) and alpha-melanocyte stimulating hormone (alpha-MSH) are two epidermal factors whose synthesis is stimulated by UV exposure. Both factors enable human melanocytes to overcome UV-induced G1 arrest and stimulate melanogenesis. Recently, we demonstrated that ET-1 and apha-MSH increase the survival of UV-irradiated melanocytes by inhibiting apoptosis. We found that cultured human melanocytes that express loss-of-function mutations in the melanocortin 1 receptor, the receptor for alpha-MSH, have increased susceptibility to killing by UVR. We attribute this increased sensitivity to UV exposure to extensive DNA damage that overwhelms the repair capacity of those cells, and to inability to fully activate survival pathways. These mutations have been associated with poor tanning ability, and increased risk for melanoma and non-melanoma skin cancers, independently of skin or hair color. We hypothesize that ET- 1 and alpha-MSH promote human melanocyte survival by inhibiting apoptosis and reducing the extent of UVB-induced DNA damage. We propose to investigate the ability of ET-1 and/or a-MSH to limit the extent of UVB-induced DNA damage and/or to enhance the rate of DNA repair. We will also determine the capacity of ET-1 and alpha-MSH to activate the Akt/PKBdependent survival pathway. Activated Akt/PKB is known to inhibit apoptosis by phosphorylating and inactivating its substrates Bad and caspase 9, and by activating NFkB and CREB. Additionally, we plan to elucidate whether the survival effects of ET-1 and/or alpha-MSH involve activation of the transcription factor Mitf, which upregulates Bcl2 expression, by modulating the activities of ERK1/2, p38 and JNK/SAPK, and CREB in UVB-irradiated melanocytes. Determining the differences in the ability of melanocytes from different pigmentary phenotypes to respond to survival factors is significant for assessing the magnitude of the cytotoxic and genotoxic effects of UVR in the skin. Also, assessing the differential sensitivity to the survival effects of a-MSH and ET-1 can be used as a reliable marker for determining individual risk to skin cancer, particularly melanoma.